Novel use of peptide compounds for treating pain in painful diabetic neuropathy

ABSTRACT

The present invention concerns the use of compounds for treating pain in painful diabetic neuropathy, preferably in diabetic distal sensory polyneuropathy.

The present invention is directed to the use of a class of peptidecompounds for treating pain in painful diabetic neuropathy, preferablyin diabetic distal sensory polyneuropathy.

Certain peptides are known to exhibit central nervous system (CNS)activity and are useful in the treatment of epilepsy and other CNSdisorders. These peptides which are described in the U.S. Pat. No.5,378,729 have the Formula (Ia):

whereinR is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or electron donating group;R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl,lower cycloalkyl lower alkyl, each unsubstituted or substituted with anelectron donating group or an electron withdrawing group; andR₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl,lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl loweralkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted or substituted withat least one electron withdrawing group or electron donating group;z is O, S, S(O)_(a), NR₄, PR₄ or a chemical bond;Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, and Y may beunsubstituted or substituted with an electron donating group or anelectron withdrawing group, provided that when Y is halo, Z is achemical bond, orZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇,NR₄SR₇, SPR₄R₅ or PR₄SR₇, NR₄PR₅R₆ or PR₄NR₅R₇,

R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may beunsubstituted or substituted with an electron withdrawing group or anelectron donating group; andR₇ is R₆ or COOR₈ or COR₈;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with an electronwithdrawing group or an electron donating group; andn is 14; anda is 1-3.

U.S. Pat. No. 5,773,475 also discloses additional compounds useful fortreating CNS disorders. These compounds areN-benzyl-2-amino-3-methoxy-propionamide having the Formula (IIa):

whereinAr is aryl which is unsubstituted or substituted with halo; R₃ is loweralkoxy; and R₁ is methyl.

The patents U.S. Pat. No. 5,378,729 and U.S. Pat. No. 5,773,475 arehereby incorporated by reference. However, neither of these patentsdescribes the use of these compounds as specific analgesics for thetreatment of pain in painful diabetic neuropathy, especially in diabeticdistal sensory polyneuropathy.

The clinical causes of neuropathic pain are widespread and include bothtrauma and disease. Different neuropathic syndromes (like diabeticneuropathy, postherpetic neuralgia, trigeminal neuralgia, postoperativepain, posttraumatic pain, HIV pain, cancer pain, etc.) are all havingdifferent underlying mechanisms/pathophysiology. The knowledge oftreatment of e.g. trauma-induced neuropathic pain does therefore notlead to treatment methods of disease-induced neuropathic pain.

WO 02/074297 relates to the use of a compound according to Formula (IIa)wherein Ar is phenyl which may be substituted by at least one halo, R₃is lower alkoxy containing 1-3 carbon atoms and R₁ is methyl for thepreparation of pharmaceutical compositions useful for the treatment ofallodynia as a major and unique pain syndrome independent of the natureof an underlying disease, but often related to peripheral neuropathicpain.

WO 02/074297 is based on the results of animal models for peripheralneuropathic pain as a result of trauma (Chung model, Bennett model). WO02/074297 does not disclose specific animal models of disease-induced(i.e. diabetic) neuropathic pain. The Chung model of peripheralneuropathic pain involves tight ligatures of spinal nerves in rats,either spinal nerves L5 or L5 and L6 (Kim and Chung, 1992, Pain50:355-363), or in primates (L7). In the Bennett model (Bennett and Xie1988, Pain 33:87-107, Bennett 1993, Muscle Nerve 16:1040-1048), amononeuropathy is produced by placing four loosely constrictiveligatures around the common sciatic nerve. Upon this ligature,hyperalgesia develops in response to noxious heat stimuli, mustard oiland to mechancial stimuli. The proportion of diabetic patients sufferingfrom allodynia is rather low compared to patients developing allodyniaas a result of postherpetic neuralgia or posttraumatic neuralgia.Therefore, the animal models used in WO 02/074297 are not suitable asmodels of disease-induced (diabetic) neuropathic pain, e.g. foridentifying compounds for prevention, alleviation or/and treatment ofdiabetic neuropathic pain. In particular, these models are not suitablefor identifying effective dosing and plasma levels in man forprevention, alleviation or/and treatment of diabetic neuropathic pain.

WO 02/15922 describes the evaluation of(2R)-(2-acetyl-amino)-N-[(4-fluorophenyl)methyl]-3-methoxypropanamide bythe Chung model of peripheral neuropathic pain. Like WO 02/074297, thisdocument does not disclose specific studies in animal models ofdisease-induced (diabetic) neuropathic pain. In WO 02/15922, there is nodisclosure of compounds useful for prevention, alleviation or/andtreatment of diabetic neuropathic pain.

The inventors of the present invention published initial results of SPM927 in the treatment of diabetic neuropathy, indicating that SPM 927 issuperior to placebo in reducing the patient's daily pain scores(Hovinga, IDrugs 2003, 6 (5):479-485). However, effective treatmentschedules and dosages are not disclosed. Further, there is no indicationfrom which type or stage of diabetes the patients have suffered.

The inventors of the present invention also published an open label 25patient trial with SPM 927 in subjects with resistant neuropathic pain,mainly radicular pain (McCleane et al., Neuroscience Letters 352 (2003),117-120). The outcome of this trial was that SPM 927 may have ananalgesic effect on human neuropathic pain. As this trial did notinclude any patient with diabetic neuropathy, no information on thispatient population was gathered. As mentioned above, the differentneuropathic pain populations are having different underlyingpathophysiologies.

WO 02/074784 relates to the use of a compound having Formula (Ia) or/andFormula (IIa) showing antinociceptive properties for treating differenttypes and symptoms of acute and chronic pain, especially non neuropathicinflammatory pain, e.g. rheumatoid arthritic pain or/and secondaryinflammatory osteo-arthritic pain.

Pain is a subjective experience and the perception of pain is performedin particular parts of the Central Nervous System (CNS). Usually noxious(peripheral) stimuli are transmitted to the Central Nervous System (CNS)beforehand, but pain is not always associated with nociception. A broadvariety of different types of clinical pain exists, that are derivedfrom different underlying pathophysiological mechanisms and that willneed different treatment approaches.

The perception of pain may be characterized by three major types ofclinical pain:

-   -   acute pain    -   chronic pain    -   neuropathic pain

Acute clinical pain may result from inflammation or soft tissue injury,for instance. This type of pain is adaptive and has the biologicallyrelevant function of warning and enabling healing and repair of analready damaged body part to occur undisturbed. A protective function isachieved by making the injured/inflamed area and surrounding tissuehypersensitive to all stimuli so that contact with any external stimulusis avoided. The neuronal mechanisms underlying this type of clinicalpain are fairly well understood and pharmacological control of acuteclinical pain is available and effective by means of e.g. Non-SteroidalAnti-inflammatory Drugs (NSAIDs) up to opioids depending on type andextension of the sensation.

Chronic clinical pain appears as sustained sensory abnormalitiesresulting from an ongoing peripheral pathology such as cancer or chronicinflammation (e.g. arthritis) or it can be independent of the initiatingtriggers. The latter being maladaptive, offering no survival advantageand very often no effective treatment is available.

There are several causes of human neuropathy with considerablevariability in symptoms and neurological deficits. Painful neuropathiesare defined as neurological disorders characterised by persistence ofpain and hypersensitivity in a body region, of which the sensoryinnervation has been damaged, but damage to sensory nerves does notalways produce neuropathic pain, usually loss of sensation rather thanhypersensitivity or pain are observed.

Neuropathic pain can be classified as peripheral and central neuropathicpain. Peripheral neuropathic pain is caused by injury or infection ofperipheral sensory nerves, whereas central neuropathic pain is caused bydamage to the CNS or/and the spinal cord. Both peripheral and centralneuropathic pain can occur without obvious initial nerve damage.

Common analgesics like opioids and non-steroidal anti-inflammatory drugs(NSAIDs) improve only insufficiently chronic abnormal pain syndromes asperipheral and central neuropathic pain due to insufficient efficacy orlimiting side effects. In the search for alternative treatment regimesto produce satisfactory and sustained pain relief, corticosteroids,conduction blockade, glycerol, antidepressants, local anesthetics,gangliosides and electrostimulation have been tried, but mainlyanti-convulsants have been found useful against various types ofperipheral neuropathic pain conditions. A subset of patients withneuropathic pain responds to opioids. Gabapentin or pregabalin iseffective in reducing pain in patients with diabetic neuropathy.However, pregabalin, for instance, induces weight gain in Type I or IIdiabetes patients by edema formation. Increased weight is an establishedrisk factor for cardiovascular disease, in particular in Type IIdiabetic patients.

The mechanisms of neuropathic pain in diabetic patients are poorlyunderstood. Current treatments use a variety of pharmacological,surgical, physical and psychological approaches. However, the evidencefor many of the treatments is still limited.

Pain derived from a diabetic sensory neuropathy is the most common formof diabetic neuropathy. It is usually of insidious onset. Predominantpain may be combined with temperature and tactile loss. The pain isusually aching, prickling, or burning in quality with superimposedstabs, and often most troublesome at night. The pain is feltpredominantly in the lower limbs, however, with occurence also at theupper limbs and trunk.

If general overactivity and unleaded low threshold activation of sensoryneurons is considered as one of the main syndroms of neuropathy andneuropathic pain sensation with a marked mechanoallodynia as the mostdisabling clinical sympton, selective inhibition of thispathophysiological event instead of general inhibition of high thresholdnoxious stimuli (by e.g. local anesthetics) of the normal sensorynociception provides clear advantages.

The use of compounds of Formula (Ib) or/and Formula (IIb) for treatmentof pain in painful diabetic neuropathy has not been reported. Thus, thepresent invention concerns the use of said compounds of Formulae (Ib)or/and (IIb) for the preparation of a pharmaceutical composition for theprevention, alleviation or/and treatment of diabetic pain such as painassociated with all types of painful diabetic neuropathy, especially,but not limited to, for the prevention, alleviation or/and treatment ofpain associated with diabetic distal sensory polyneuropathy. Preferably,the painful diabetic neuropathy is associated with Diabetes mellitusType I or Type II, more preferably with Diabetes mellitus Type II.

Surprisingly, application of compounds (Ib) or/and (IIb), particularly(R)-2-acetamide-N-benzyl-3-methoxypropionamide (SPM 927) exhibited astatistically significant and clinically meaningful efficacy in reducingpain in subjects with painful diabetic neuropathy in a randomized doubleblind placebo controlled trial. Testing of diabetic neuropathy has notbeen conducted previously, either in animals or in humans. This is thefirst time that the efficacy of SPM 927 in diabetic neuropathic pain inhumans has been evaluated. The patients included in the trial hadclinically diagnosed pain attributed to diabetic distal sensorypolyneuropathy and a diagnosis of Diabetes mellitus (Type I or Type II).The patients had good or fair diabetic control which was optimized forat least 3 months prior to the start of the trial. Surprisingly, SPM 927did not induce weight gain in Diabetes mellitus Type I and II patients,which is of particular importance for drugs to be administered toDiabetes mellitus Type II patients. Weight gain and/or obesity (whichmay be induced by drugs) is an established risk factor forcardiovascular disease (Schemthaner 1996, Diabetes Res. Clin. Pract1996, 31: S3-S13), in particular in Diabetes mellitus Type II patients.

In particular, when compared to placebo treated diabetic patients,diabetic patients treated with the compounds (Ib) or/and (IIb),particularly SPM 927, had a reduced average daily pain, overall pain,present pain intensity and pain interference with sleep. Treatment withSPM 927 was associated with an improvement in the subjects' perceptionof pain interference with general activity, the patients' globalimpression of change in pain, clinical global impression of change inpain, the subject's perception of different neuropathic pain qualities,quality of life and proportion of pain-free days. The analysis of safetydata revealed no serious safety issues. In particular, no interferencewas observed with the treatment for diabetes control.

The invention is applicable in animals, particularly mammals includinghumans.

A compound according to the invention useful for the prevention,alleviation or/and treatment of pain associated with painful diabeticneuropathy, especially associated with diabetic distal sensorypolyneuropathy, or/and for the prevention, alleviation or/and treatmentof a condition of pain associated with painful diabetic neuropathy whichis, for example, average daily pain, overall pain, present painintensity, pain interference with sleep, the subjects' perception ofpain interference with general activity, the patients' global impressionof change in pain, clinical global impression of change in pain, thesubject's perception of different neuropathic pain qualities, quality oflife and proportion of pain-free days, has the general Formula (Ib)

whereinR is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryllower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup, and/or at least one electron donating group;R₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl loweralkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic,heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, eachunsubstituted or substituted with at least one electron donating groupand/or at least one electron withdrawing group;andR₂ and R₃ are independently hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic loweralkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyllower alkyl, or Z-Y wherein R₂ and R₃ may be unsubstituted orsubstituted with at least one electron withdrawing group and/or at leastone electron donating group;Z is O, S, S(O)_(a), NR₄, NR′₆, PR₄ or a chemical bond;Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, loweralkynyl, halo, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic and Y may be unsubstituted or substituted with at least oneelectron donating group and/or at least one electron withdrawing group,provided that when Y is halo, Z is a chemical bond, orZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅, PR₄OR₅, SNR₄R₇,NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇ or N⁺R₅R₆R₇,

R′₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl which maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group;R₄, R₅ and R₆ are independently hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ mayindependently be unsubstituted or substituted with at least one electronwithdrawing group or/and at least one electron donating group;R₇ is R₆ or COOR₈ or COR₈, which R₇ may be unsubstituted or substitutedwith at least one electron withdrawing group or/and at least oneelectron donating group;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;andn is 1-4; anda is 1-3.

Preferably the compound according has the general Formula (IIb)

whereinAr is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one halo; R₃ is —CH₂-Q, wherein Q is lower alkoxy; and R₁is lower alkyl, especially methyl.

The present invention is also directed to a pharmaceutical compositioncomprising a compound according to Formula (Ib) or/and Formula (IIb)useful for the prevention, alleviation or/and treatment of painassociated with painful diabetic neuropathy, especially associated withdiabetic distal sensory polyneuropathy, or/and for the prevention,alleviation or/and treatment of a condition of pain associated withpainful diabetic neuropathy which is, for example, average daily pain,overall pain, present pain intensity, pain interference with sleep, thesubjects' perception of pain interference with general activity, thepatients' global impression of change in pain, clinical globalimpression of change in pain, the subject's perception of differentneuropathic pain qualities, quality of life and proportion of pain-freedays, and to the preparation of said pharmaceutical composition.Preferably, the painful diabetic neuropathy is associated with Diabetesmellitus Type I or Type II, more preferably with Diabetes mellitus TypeII.

The compounds of Formula (Ia) are described in U.S. Pat. No. 5,378,729,the contents of which are incorporated by reference.

The “lower alkyl” groups when used alone or in combination with othergroups, are lower alkyl containing from 1 to 6 carbon atoms, especially1 to 3 carbon atoms, and may be straight chain or branched. These groupsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, amyl, hexyl, and the like.

The “lower alkoxy” groups are lower alkoxy containing from 1 to 6 carbonatoms, especially 1 to 3 carbon atoms, and may be straight chain orbranched. These groups include methoxy, ethoxy, propoxy, butoxy,isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

The “aryl lower alkyl” groups include, for example, benzyl, phenylethyl,phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl,1,1-diphenylethyl, 1,2-diphenylethyl, and the like.

The term “aryl”, when used alone or in combination, refers to anaromatic group which contains from 6 up to 18 ring carbon atoms and upto a total of 25 carbon atoms and includes the polynuclear aromatics.These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclicand are fused rings. A polynuclear aromatic compound as used herein, ismeant to encompass bicyclic and tricyclic fused aromatic ring systemscontaining from 10-18 ring carbon atoms and up to a total of 25 carbonatoms. The aryl group includes phenyl, and the polynuclear aromaticse.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Thearyl group also includes groups like ferrocenyl. Aryl groups may beunsubstituted or mono or polysubstituted with electron withdrawingor/and electron donating groups as described below.

“Lower alkenyl” is an alkenyl group containing from 2 to 6 carbon atomsand at least one double bond. These groups may be straight chained orbranched and may be in the Z or E form. Such groups include vinyl,propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl,(E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl,pentadienyl, e.g., 1, 3 or 2,4-pentadienyl, and the like.

The term “lower alkynyl” is an alkynyl group containing 2 to 6 carbonatoms and may be straight chained as well as branched. It includes suchgroups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl and the like.

The term “lower cycloalkyl” when used alone or in combination is acycloalkyl group containing from 3 to 18 ring carbon atoms and up to atotal of 25 carbon atoms. The cycloalkyl groups may be monocyclic,bicyclic, tricyclic, or polycyclic and the rings are fused. Thecycloalkyl may be completely saturated or partially saturated. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl,cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenchyl, pinenyl,adamantyl, and the like. Cycloalkyl includes the cis or trans forms.Cycloalkyl groups may be unsubstituted or mono or polysubstituted withelectron withdrawing or/and electron donating groups as described below.Furthermore, the substituents may either be in endo or exo positions inthe bridged bicyclic systems.

The term “electron-withdrawing and electron donating” refer to theability of a substituent to withdraw or donate electrons, respectively,relative to that of hydrogen if the hydrogen atom occupied the sameposition in the molecule. These terms are well understood by one skilledin the art and are discussed in Advanced Organic Chemistry, by J. March,John Wiley and Sons, New York, N.Y., pp. 16-18 (1985) and the discussiontherein is incorporated herein by reference. Electron withdrawing groupsinclude halo, including bromo, fluoro, chloro, iodo and the like; nitro,carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl,quaternary ammonium, haloalkyl such as trifluoromethyl, aryl loweralkanoyl, carbalkoxy and the like. Electron donating groups include suchgroups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like;lower alkyl, such as methyl, ethyl, and the like; amino, loweralkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto,lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) andthe like. One of ordinary skill in the art will appreciate that some ofthe aforesaid substituents may be considered to be electron donating orelectron withdrawing under different chemical conditions. Moreover, thepresent invention contemplates any combination of substituents selectedfrom the above-identified groups.

The term “halo” includes fluoro, chloro, bromo, iodo and the like.

The term “acyl” includes lower alkanoyl containing from 1 to 6 carbonatoms and may be straight chains or branched. These groups include, forexample, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiarybutyryl, pentanoyl and hexanoyl.

As employed herein, a heterocyclic group contains at least one sulfur,nitrogen or oxygen ring atom, but also may include several of said atomsin the ring. The heterocyclic groups contemplated by the presentinvention include heteroaromatics and saturated and partially saturatedheterocyclic compounds. These heterocyclics may be monocyclic, bicyclic,tricyclic or polycyclic and are fused rings. They may preferably containup to 18 ring atoms and up to a total of 17 ring carbon atoms and atotal of up to 25 carbon atoms. The heterocyclics are also intended toinclude the so-called benzoheterocyclics. Representative heterocyclicsinclude furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl,indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl,pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl,benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl,pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl,imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl,pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino,oxetanyl, azetidinyl, the N-oxides of the nitrogen containingheterocycles, such as the N-oxides of pyridyl, pyrazinyl, andpyrimidinyl and the like. Heterocyclic groups may be unsubstituted ormono or polysubstituted with electron withdrawing or/and electrondonating groups.

The preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl,benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl,imidazolyl, pyrimidinyl, or pyridazinyl. The preferred heterocyclic is a5 or 6-membered heterocyclic compound. The especially preferredheterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, orpyridazinyl. The most preferred heterocyclics are furyl and pyridyl.

The preferred compounds are those wherein n is 1, but di (n=2), tri(n=3) and tetrapeptides (n=4) are also contemplated to be within thescope of the invention.

The preferred values of R is aryl lower alkyl, especially benzylespecially those wherein the phenyl ring thereof is unsubstituted orsubstituted with electron donating groups or/and electron withdrawinggroups, such as halo (e.g., F).

The preferred R₁ is H or lower alkyl. The most preferred R₁ group ismethyl.

The preferred electron donating substituents or/and electron withdrawingsubstituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl,carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide,heterocyclic, guanidine, quaternary ammonium, lower alkenyl, loweralkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(loweralkyl) amino, amino lower alkyl, mercapto,mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide”encompasses mercapto, mercapto alkyl and alkylthio, while the termdisulfide encompasses alkyldithio. Especially preferred electrondonating or/and electron withdrawing groups are halo or lower alkoxy,most preferred are fluoro or methoxy. These preferred substituents maybe present on any one of the groups in Formula (Ib) or/and (IIb), e.g.R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₅₀ and/or R₈ as defined herein.

The ZY groups representative of R₂ and R₃ include hydroxy, alkoxy, suchas methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such asthiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino;alkylamino, such as methylamino, ethylamino; arylamino, such as anilino;lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt,hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino,N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino,aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino(—NH—OH), lower alkoxy amino [(NHOR₁₈) wherein R₁₈ is lower alkyl],N-lower alkylhydroxyl amino [(NR₁₈)OH wherein R₁₈ is lower alkyl],N-lower alkyl-O-lower alkylhydroxyamino, i.e., [N(R₁₈)OR₁₉ wherein R₁₈and R₁₉ are independently lower alkyl], and o-hydroxylamino (—O—NH₂);alkylamido such as acetamido; trifluoroacetamido; lower alkoxyamino,(e.g., NH(OCH₃); and heterocyclicamino, such as pyrazoylamirio.

The preferred heterocyclic groups representative of R₂ and R₃ aremonocyclic 5- or 6-membered heterocyclic moieties of the formula:

or those corresponding partially or fully saturated form thereof whereinn is 0 or 1; andR₅₀ is H or an electron withdrawing group or electron donating group;A, E, L, J and G are independently CH, or a heteroatom selected from thegroup consisting of N, O, S;but when n is 0, G is CH, or a heteroatom selected from the groupconsisting of NH, O and S with the proviso that at most two of A, E, L,J and G are heteroatoms.

When n is 0, the above heteroaromatic moiety is a five membered ring,while if n is 1, the heterocyclic moiety is a six membered monocyclicheterocyclic moiety. The preferred heterocyclic moieties are thoseaforementioned heterocyclics which are monocyclic.

If the ring depicted hereinabove contains a nitrogen ring atom, then theN-oxide forms are also contemplated to be within the scope of theinvention.

When R₂ or R₃ is a heterocyclic of the above formula, it may be bondedto the main chain by a ring carbon atom. When n is 0, R₂ or R₃ mayadditionally be bonded to the main chain by a nitrogen ring atom.

Other preferred moieties of R₂ and R₃ are hydrogen, aryl, e.g., phenyl,aryl alkyl, e.g., benzyl and alkyl.

It is to be understood that the preferred groups of R₂ and R₃ may beunsubstituted or mono or poly substituted with electron donating or/andelectron withdrawing groups. It is preferred that R₂ and R₃ areindependently hydrogen, lower alkyl, which is either unsubstituted orsubstituted with electron withdrawing groups or/and electron donatinggroups, such as lower alkoxy (e.g., methoxy, ethoxy, and the like),N-hydroxylamino, N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyland alkylhydroxyamino.

It is preferred that one of R₂ and R₃ is hydrogen.

It is preferred that n is one.

It is more prefered that n=1 and one of R₂ and R₃ is hydrogen. It isespecially preferred that in this embodiment, R₂ is hydrogen and R₃ islower alkyl or ZY; Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl; ZYis NR₄NR₅R₇, NR₄OR₅, ONR₄R₇,

In another especially preferred embodiment, n=1, R₂ is hydrogen and R₃is lower alkyl which may be substituted or unsubstituted with anelectron donating or electron withdrawing group, NR₄OR, or ONR₄R₇.

In yet another especially preferred embodiment, n=1, R₂ is hydrogen andR₃ is lower alkyl which is unsubstituted or substituted with hydroxy orloweralkoxy, NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independentlyhydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may beunsubstituted or substituted with an electron withdrawing group and R₁is lower alkyl. In this embodiment it is most preferred that aryl isphenyl, which is unsubstituted or substituted with halo.

It is preferred that R₂ is hydrogen and R₃ is hydrogen, an alkyl groupwhich is unsubstituted or substituted by at least an electron donatingor electron withdrawing group or ZY. In this preferred embodiment, it ismore preferred that R₃ is hydrogen, an alkyl group such as methyl, whichis unsubstituted or substituted by an electron donating group, or NR₄ORor ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen or loweralkyl. It is preferred that the electron donating group is lower alkoxy,and especially methoxy or ethoxy.

It is preferred that R₂ and R₃ are independently hydrogen, lower alkyl,or ZY;

Z is O, NR₄ or PR₄;

Y is hydrogen or lower alkyl or

It is also preferred that R is aryl lower alkyl. The most preferred arylfor R is phenyl. The most preferred R group is benzyl. In a preferredembodiment, the aryl group may be unsubstituted or substituted with anelectron donating or electron withdrawing group. If the aryl ring in Ris substituted, it is most preferred that it is substituted with anelectron withdrawing group, especially on the aryl ring. The mostpreferred electron withdrawing group for R is halo, especially fluoro.

The preferred R₁ is lower alkyl, especially methyl.

It is more preferred that R is aryl lower alkyl and R₁ is lower alkyl.

Further preferred compounds are compounds of Formula (Ib) wherein n is1; R₂ is hydrogen; R₃ is hydrogen, a lower alkyl group, especiallymethyl which is substituted by an electron donating or electronwithdrawing group or ZY; R is aryl, aryl lower alkyl, such as benzyl,wherein the aryl group is unsubstituted or substituted with an electrondonating or electron withdrawing group and R₁ is lower alkyl. In thisembodiment, it is more preferred that R₃ is hydrogen, a lower alkylgroup, especially methyl, which may be substituted by electron donatinggroup, such as lower alkoxy, (e.g., methoxy, ethoxy and the like),NR₄OR₅ or ONR₄R₇ wherein these groups are defined hereinabove.

The most preferred compounds utilized are those of the Formula (IIb):

whereinAr is aryl, especially phenyl, which is unsubstituted or substitutedwith at least one electron donating group or electron withdrawing group,especially halo,R₁ is lower alkyl, especially containing 1-3 carbon atoms; andR₃ is as defined herein, but especially hydrogen, loweralkyl, which isunsubstituted or substituted by at least an electron donating group orelectron withdrawing group or ZY. It is even more preferred that R₃ is,in this embodiment, hydrogen, an alkyl group which is unsubstituted orsubstituted by an electron donating group, NR₄OR₅ or ONR₄R₇. It is mostpreferred that R₃ is CH₂-Q, wherein Q is lower alkoxy, especiallycontaining 1-3 carbon atoms; NR₄OR₅ or ONR₄R₇ wherein R₄ is hydrogen oralkyl containing 1-3 carbon atoms, R₅ is hydrogen or alkyl containing1-3 carbon atoms, and R₇ is hydrogen or alkyl containing 1-3 carbonatoms.

The most preferred R₁ is CH₃. The most preferred R₃ is CH₂-Q, wherein Qis methoxy.

The most preferred aryl is phenyl. The most preferred halo is fluoro.

The most preferred compounds include:

-   (R)-2-acetamido-N-benzyl-3-methoxy-propionamide;-   O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;-   O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;-   N-acetyl-D-phenylglycine benzylamide;-   D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid    benzylamide;-   D-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide.

It is to be understood that the various combinations and permutations ofthe Markush groups of R₁, R₂, R₃, R and n described herein arecontemplated to be within the scope of the present invention. Moreover,the present invention also encompasses compounds and compositions whichcontain one or more elements of each of the Markush groupings in R₁, R₂,R₃, n and R and the various combinations thereof. Thus, for example, thepresent invention contemplates that R₁ may be one or more of thesubstituents listed hereinabove in combination with any and all of thesubstituents of R₂, R₃, and R with respect to each value of n.

The compounds utilized in the present invention may contain one or moreasymmetric carbons and may exist in racemic and optically active forms.

The configuration around each asymmetric carbon can be either the D or Lform. It is well known in the art that the configuration around a chiralcarbon atoms can also be described as R or S in the Cahn-Prelog-Ingoldnomenclature system. All of the various configurations around eachasymmetric carbon, including the various enantiomers and diastereomersas well as racemic mixtures and mixtures of enantiomers, diastereomersor both are contemplated by the present invention.

In the principal chain, there exists asymmetry at the carbon atom towhich the groups R₂ and R₃ are attached. When n is 1, the compounds ofthe present invention is of the formula

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, R′₆, R₇, R₈, R₅₀, Z and Y are asdefined previously.

As used herein, the term configuration shall refer to the configurationaround the carbon atom to which R₂ and R₃ are attached, even thoughother chiral centers may be present in the molecule. Therefore, whenreferring to a particular configuration, such as D or L, it is to beunderstood to mean the D or L stereoisomer at the carbon atom to whichR₂ and R₃ are attached. However, it also includes all possibleenantiomers and diastereomers at other chiral centers, if any, presentin the compound.

The compounds of the present invention are directed to all the opticalisomers, i.e., the compounds of the present invention are either theL-stereoisomer or the D-stereoisomer (at the carbon atom to which R₂ andR₃ are attached). These stereoisomers may be found in mixtures of the Land D stereoisomer, e.g., racemic mixtures. The D stereoisomer ispreferred.

More preferred is a compound of Formula (III) in the R configuration,preferably substantially enantiopure, wherein the substituent R isbenzyl which is unsubstituted or substituted with at least one halogroup, wherein R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and wherein R₁ is methyl. Preferably R is unsubstitutedbenzyl or benzyl substituted with at least one halo group which is afluoro group.

Depending upon the substituents, the present compounds may form additionsalts as well. All of these forms are contemplated to be within thescope of this invention including mixtures of the stereoisomeric forms.

The manufacture of the utilized compounds is described in U.S. Pat. Nos.5,378,729 and 5,773.475, the contents of both of which are incorporatedby reference.

The compounds utilized in the present invention are useful as such asdepicted in the Formulae (Ib) or/and (IIb) or can be employed in theform of salts in view of its basic nature by the presence of the freeamino group. Thus, the compounds of Formulae (Ib) or/and (IIb) formsalts with a wide variety of acids, inorganic and organic, includingpharmaceutically acceptable acids. The salts with therapeuticallyacceptable acids are of course useful in the preparation of formulationwhere enhanced water solubility is most advantageous.

These pharmaceutically acceptable salts have also therapeutic efficacy.These salts include salts of inorganic acids such as hydrochloric,hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid andsulfuric acids as well as salts of organic acids, such as tartaric,acetic, citric, malic, benzoic, perchloric, glycolic, gluconic,succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids,benzenesulfonic), phosphoric, malonic, and the like.

The present invention is further directed to a method for theprevention, alleviation or/and treatment of a disease or condition asdescribed above in a mammal, including a human being, comprisingadministering at least one compound of Formulae (Ib) or/and (IIb).

It is preferred that the compound utilized in the present invention isused in therapeutically effective amounts.

The physician will determine the dosage of the present therapeuticagents which will be most suitable and it will vary with the form ofadministration and the particular compound chosen, and furthermore, itwill vary with the patient under treatment, the age of the patient, thetype of malady being treated. He will generally wish to initiatetreatment with small dosages substantially less than the optimum dose ofthe compound and increase the dosage by small increments until theoptimum effect under the circumstances is reached. When the compositionis administered orally, larger quantities of the active agent will berequired to produce the same effect as a smaller quantity givenparenterally. The compounds are useful in the same manner as comparabletherapeutic agents and the dosage level is of the same order ofmagnitude as is generally employed with these other therapeutic agents.

In a preferred embodiment, the compounds of the present invention areadministered in amounts ranging from about 1 mg to about 100 mg perkilogram of body weight per day, more preferred in amounts ranging fromabout 1 mg to about 10 mg per kilogram of body weight per day. Thisdosage regimen may be adjusted by the physician to provide the optimumtherapeutic response. Patients in need thereof may be treated with dosesof the compound of the present invention of at least 50 mg/day,preferably of at least 200 mg/day, more preferably of at least 300mg/day and most preferably of at least 400 mg/day. At the maximum, apatient in need thereof may be treated with doses at a maximum of 3g/day, more preferably a maximum of 1 g/day and most preferably amaximum of 600 mg/day.

In another preferred embodiment, the daily doses are increased until apredetermined daily dose is reached which is maintained during thefurther treatment.

In yet another preferred embodiment, several divided doses may beadministered daily, or the dose may be proportionally reduced asrequired by the exigencies of the therapeutic situation. For example,three doses per day may be administered, preferably two doses per day.It is more preferred to administer a single dose per day.

In yet another preferred embodiment, an amount of the compounds of thepresent invention may be administered which results in a plasmaconcentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5 μg/ml (peak),calculated as an average over a plurality of treated subjects.

The compounds of Formulae (Ib) or/and (IIb) may be administered in aconvenient manner, such as by oral, intravenous (where water soluble),intramuscular, intrathecal or subcutaneous routes. Oral administrationis preferred.

The pharmaceutical composition of the present invention may be preparedfor the treatment regimen as described above, in particular for thetreatment with doses as described above, to effect plasma concentrationsas described above, for administration periods or/and administrationroutes as specified in the embodiments of the present invention asdescribed above.

In another preferred embodiment, the method of the present invention asdescribed above for the treatment of a mammal including a human being inneed thereof comprises administering a compound of the present inventionin combination with administering an active agent for the prevention,alleviation or/and treatment of Diabetes mellitus Type I or Type II,preferably Type II. The compound of the present invention and the activeagent for the preparation, alleviation or/and treatment of Diabetesmellitus may be administered together, i.e. in a single dose form, ormay be administered separately, i.e. in a separate dose form. Thus, thepharmaceutical composition of the present invention may comprise acompound of the present invention as defined above and may furthercomprise an active agent for the prevention, alleviation or/andtreatment of Diabetes mellitus Type I or Type II, preferably Type II.The pharmaceutical composition may comprise a single dose form or maycomprise a separate dose form comprising a first composition comprisinga compound of the present invention as defined above and a secondcomposition for the prevention, alleviation, or/and treatment ofDiabetes mellitus Type I or Type II, preferably Type II.

The active agent for the prevention, alleviation or/and treatment ofDiabetes mellitus Type I or Type II, preferably Type II, is preferablyan agent which does not induce weight gain in the patients in needthereof.

The compounds of the present invention may be used for the preparationof a pharmaceutical composition as described above.

The compounds of Formulae (Ib) or/and (IIb) may be orally administered,for example, with an inert diluent or with an assimilable ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,or it may be compressed into tablets, or it may be incorporated directlyinto the fool of the diet. For oral therapeutic administration, theactive compound of Formulae (Ib) or/and (IIb) may be incorporated withexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 1% of activecompound of Formulae (Ib) or/and (IIb). The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 5 to about 80% of the weight of the unit.The amount of active compound of Formulae (Ib) or/and (IIb) in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention contains between about 10 mg and 6 g active compoundof Formulae (Ib) or/and (IIb).

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or otherwise modifythe physical form of the dosage unit. For instance, tablets, pills, orcapsules may be coated with shellac, sugar or both. A syrup or elixirmay contain the active compound, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and flavoring such as cherryor orange flavor. Of course, any material used in preparing any dosageunit form should be pharmaceutically pure and substantially non-toxic inthe amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and formulations. Forexample, sustained release dosage forms are contemplated wherein theactive ingredient is bound to an ion exchange resin which, optionally,can be coated with a diffusion barrier coating to modify the releaseproperties of the resin.

The active compound may also be administered parenterally orintraperitoneally. Dispersions can also be prepared in glycerol, liquid,polyethylene glycols, and mixtures thereof and in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases the form must be sterile and mustbe fluid to the extent that easy syringability exists. It must be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying the freeze-dryingtechnique plus any additional desired ingredient from previouslysterile-filtered solution thereof.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagent, isotonic and absorption delaying agents for pharmaceutical activesubstances as well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active ingredient, its use inthe therapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions indosage unit form or ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the mammalian subjects to be treated; eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. The specifics for the novel dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active material an the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such as active material for the treatment ofdisease in living subjects having a diseased condition in which bodilyhealth is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient andeffective administration in effective amounts with a suitablepharmaceutically acceptable carrier in dosage unit form as hereinbeforedescribed. A unit dosage form can, for example, contain the principalactive compound in amounts ranging from about 10 mg to about 6 g.Expressed in proportions, the active compound is generally present infrom about 1 to about 750 mg/ml of carrier. In the case of compositionscontaining supplementary active ingredients, the dosages are determinedby reference to the usual dose and manner of administration of the saidingredients.

As used herein the term “patient” or “subject” refers to a warm bloodedanimal, and preferably mammals, such as, for example, cats, dogs,horses, cows, pigs, mice, rats and primates, including humans. Thepreferred patient is humans.

The term “treat” refers to either relieving the pain associated with adisease or condition or alleviating the patient's disease or condition.

The compounds of the present invention are administered to a patientsuffering from the aforementioned type of pain in an analgesic effectiveamount. These amounts are equivalent to the therapeutically effectiveamounts described hereinabove.

The following example shows the properties of SPM 927 in reducing painin a clinical trial in subjects with painful diabetic neuropathy, inparticular with diabetic distal sensory neuropathy.

The used substance was SPM 927 which is the synonym for Harkoseride. Thestandard chemical nomenclature is(R)-2-acetamide-N-benzyl-3-methoxypropionamide. The internationalnon-proprietory name of SPM 927 is lacosamide.

EXAMPLE

A randomized, double-blind placebo controlled trial to investigatesafety and efficacy of SPM 927 in painful diabetic neuropathy wasformed.

Objectives: The primary objective of the study was to determine whetherSPM 927 was effective in reducing pain in subjects with diabetic distalsensory polyneuropathy.

Secondary objectives were the following:

-   -   To investigate how SPM 927 affects different qualities of        neuropathic pain    -   To investigate whether SPM 927 affects sleep and activity in        subjects suffering from diabetic distal sensory polyneuropathy    -   To investigate whether SPM 927 influences the Quality of Life        and the Profile of Mood States    -   To further investigate the tolerability and safety of SPM 927    -   To investigate the pre- and post-dose plasma concentrations of        unchanged SPM 927

Methodology: This was a multicenter, double-blind, placebo-controlledtrial to assess the efficacy, safety, tolerability, and pre- andpost-dose plasma concentrations of oral SPM 927 in subjects with painfuldiabetic neuropathy.

Baseline data were collected during the last week of the 4-week Run-InPhase to ensure subject eligibility. Eligible subjects were thenrandomized to receive a maximum of 400 mg per day of SPM 927 (startingat 100 mg/day for 3 weeks, then titrating up at 100 mg intervals for 3weeks) or placebo. The highest attained dose was maintained for 4 weeksduring the Maintenance Phase, after which subjects entered the TaperPhase and were tapered off of study medication for 1 week. The TaperPhase was followed by a 2-week Safety Follow-Up Phase.

Number of subjects (planned and analyzed): A total of 140 subjects wereplanned to be enrolled in order to achieve 100 evaluable subjects. Atotal of 438 subjects were screened for this trial. Two hundredseventy-seven were screen failures due to stringent entry criteria, and42 were Run-In failures. Therefore, a total of 119 subjects wererandomized. All 119 subjects who were randomized also received at leastone dose of trial medication and are referred to as the Safety Set (SS).All randomized subjects also had at least one post-Baseline efficacyassessment and are considered part of the Full Analysis Set (FAS).Ninety-three subjects in the FAS completed the Maintenance Phase and didnot have a major protocol violation and are, therefore, considered partof the Per Protocol Set (PPS). A total of 94 subjects completed allphases of the trial.

Diagnosis and main criteria for Inclusion: Subjects were male or female,age 18 or older. Subjects had clinically diagnosed pain attributed todiabetic distal sensory polyneuropathy for 1-5 years and a diagnosis ofdiabetes mellitus (Type I or Type II). Subjects had at least moderatepain (mean pain intensity during the Baseline week ≧4 out of 10 on an11-point Likert scale) which had been stable for 4 weeks prior torandomization. Furthermore, subjects had good or fair diabetic control(glycosylated hemoglobin [HbA_(1C)]<10%), which was optimized (besteffort to achieve best control) for at least three months prior to Visit1.

Test product, dose and mode of administration, batch number: Subjectstook 50 mg and 100 mg SPM 927 tablets (Schwarz Pharma AG, Germany).

Duration of treatment: After completion of screening assessments,subjects began a 4-week Run-In Phase. Eligible subjects were randomizedat Visit 3 in a 1:1 ratio to active SPM 927 or matching placebo startingwith 100 mg/day (50 mg twice daily [BID]) for three weeks. Following thetitration scheme, their dosage was escalated by 100 mg in weeklyincrements to a maximum dose of 400 mg/day (provided tolerability wassatisfactory).

The dose was up-titrated only if tolerability of the previous dose levelwas satisfactory. In the event that subjects experienced adverse eventssuch that, in the investigators judgment, the dose of SPM 927 should notbe up-titrated, subjects were permitted to either remain at theircurrent dose level or back-titrate to their previous dose level. Onlyone back-titration was permitted during the trial. Once the dose oftrial medication had been reduced, it could not be re-escalated.

Once subjects had completed the Titration Phase (i.e., after 5 weeks),subjects entered the 4-week Maintenance Phase.

If subjects reached total or sufficient pain relief with lower dosesthan 400 mg/day, after careful consideration by the investigator, theywere allowed to stay on the attained dose level in the MaintenancePhase. If adverse events were intolerable during the Titration Phase orthe first week of the Maintenance Phase (only for those subjectsreaching the 400 mg/day level), subjects could have been down-titrated,once, to the next lowest dose. Subjects were treated at 400 mg/day (orhighest dose achieved) for 4 weeks in the Maintenance Phase.

At the end of the Maintenance Phase, subjects entered the Taper Phaseand were tapered off the active medication or placebo in a blindedmanner (over a period of 1 week). Subjects on 400 mg/day decreased theirtrial medication by 200 mg during the Taper Phase. Subjects on 300mg/day reduced their dose of trial medication by 100 mg during the TaperPhase. Subjects on 100 mg/day and 200 mg/day received placebo during theTaper Phase.

Reference therapy, dose and mode of administration: Placebo was providedin matching tablets.

Criteria for Evaluation:

Efficacy: The primary variable was the within-subject change in averagedaily pain score from the Baseline week to Maintenance Phase, using an11-point Likert scale (0-10).

Secondary variables included the following:

-   -   Within-subject change in average daily pain score from the        Baseline week to the third week of titration    -   Within-subject change in average daily pain score from the        Baseline week to each week of the trial    -   Within-subject change in average daily Present Pain Intensity        from the Baseline week to each week of the trial    -   Change in subject's perception of different neuropathic pain        qualities (Neuropathic Pain Scale [NPS]) assessed at Visits 1,        3, 6, 10, 11, and 12    -   Change in subject's perception of pain interference with sleep        and activity from the Baseline week to each week of the trial.        Sleep was assessed every morning (Likert—out of Brief Pain        Inventory [BPI]), and activity was assessed every evening        (Likert—out of BPI)    -   Change in subject's perception of pain assessed at every clinic        visit, as measured by Short Form—McGill Pain Questionnaire        (SF-MPQ) in 3 sections:    -   Categorical pain rating scale, from 0 (no pain) to 3 (severe        pain)    -   Visual Analog Scale (VAS), rating pain on 100-mm scale    -   Present Pain Intensity (PPI), rating pain on a 6-point scale    -   Patient's global impression of change in pain (PGIC) completed        at Visits 6, 10, and 12    -   Clinical global impression of change in pain (CGIC) completed at        Visits 6, 10, and 12    -   Change in Short Form-36 (SF-36) Quality of Life (QOL)        questionnaire completed at Visits 1, 3, 6, 10, and 12    -   Change in Profile of Mood States (POMS) questionnaire completed        at Visits 1, 3, 6, 10, and 12    -   Proportion of pain-free days during Baseline, Titration Phase,        Maintenance Phase, and Taper Phase    -   Use (number) of rescue medication

Pharmacokinetics: Plasma concentrations of unchanged SPM 927 pre-dose(trough) and peak (i.e., 24 hours post-dose) concentrations wereevaluated.

Safety: Safety variables evaluated included adverse events, clinicallaboratory assessments, electrocardiograms (ECGs), vital signmeasurements, and physical and neurological examinations.

Statistical methods: It was determined that 46 evaluable subjects ineach treatment group would yield an 80% probability of detecting asignificant difference at a two-sided 5% level of significance if thetrue treatment effect was 1.25 units on the Likert scale with a commonstandard deviation of 2.11. A total of 70 subjects in each treatmentgroup were to be accrued to allow for subjects who dropped out duringthe 4-week Run-In Phase or could not be evaluated because of missingBaseline or follow-up observations. It was estimated that 140 subjectswould be required to enroll in order to achieve a total of 120randomized subjects and 100 evaluable subjects for the primary analysis.If the dropout rate was lower than expected, the enrollment was to bestopped before a total of 70 subjects per treatment group were accrued.

For the primary efficacy variable, an analysis of covariance (ANCOVA)with terms for treatment and investigator type was used to compare thedifference between active treatment and placebo using the BaselineLikert pain score as a covariate and the change from average Baseline toaverage Maintenance Phase Likert score as the response. The treatmentdifference was estimated on the basis of least squares mean (LSMean). Atwo-sided 95% confidence interval (CI) for the treatment difference wascalculated. As a secondary analysis, treatment-by-investigatorinteraction and/or other potential factors (age, race, sex, and Baselineseverity) were explored in the ANCOVA model.

The main effect ANCOVA model was applied to the change in average dailyLikert pain score from Baseline to the first three weeks of theTitration Phase, to the entire Titration Phase, to the Treatment Phase,and to each visit using the Baseline value as a covariate.

Results

Efficacy Results:

Efficacy results from this study consistently demonstrated astatistically significant difference between SPM 927 and placebo insubjects with painful diabetic neuropathy with regard to the primaryefficacy endpoints tested in this trial. The reduction in mean painscores following the administration of SPM 927 can be regarded asclinically meaningful. Analysis of the secondary efficacy endpointsprovided additional statistically significant and clinically relevantresults (e.g., clinically meaningful improvements in subjects' qualityof sleep and daily routine activity levels).

The primary efficacy variable for this trial was the within-subjectchange in the average daily pain score from the Baseline week to theMaintenance Phase using an 11-point Likert scale (0-10), where Baselinewas the 7-day period between Visits 2 and 3. In the Full Analysis Set(Last Observation Carried Forward, LOCF) there was a 3.11-pointreduction in pain from Baseline to the Maintenance Phase following SPM27 treatment compared with a 2.21-point reduction in pain followingplacebo treatment based on the LSMean. The difference in LSMean painscore between the two groups (0.9) was statistically significant(p=0.0390) and clinically meaningful. Analysis of the FAS (As Observed)and PPS populations for the change from Baseline to the MaintenancePhase also demonstrated greater reductions in pain following treatmentwith SPM 927 than with placebo; these differences were statisticallysignificant and clinically meaningful.

For the FAS (LOCF) and, to an even greater extent the FAS (As Observed),SPM 927 was more effective in reducing pain by visit than placebo. Bythe end of the first 3 weeks of Titration, SPM 27-treated subjects hadlower average daily pain scores than placebo-treated subjects. As thedose of SPM 927 was escalated through the remainder of the TitrationPhase and eventually stabilized during the Maintenance Phase, averagedaily pain scores were increasingly lower relative to placebo-treatedsubjects. Tapering SPM 927 was associated with subsequent increases inaverage daily pain score.

Changes in the secondary efficacy endpoints were consistent with thoseseen in the primary endpoint and provide further support for theefficacy of SPM 927 in painful diabetic neuropathy. Statisticallysignificant differences from Baseline to the Maintenance Phase followingSPM 927 treatment versus placebo were seen for the VAS (rating ofoverall pain) and present pain intensity of the SF-MPQ, subject'sperception of pain interference with sleep, and subject's perception ofpain interference with general activity. Statistically significantdifferences were also observed following SPM 927 and placebo treatmentfor CGIC and PGIC scores at the end of Maintenance Phase (Visit 10). Alarger proportion of subjects in the SPM 927 group compared with theplacebo group experienced a decrease of 2 or more points on the Likertpain scale during all phases of the trial. In addition, treatment withSPM 927 was associated with greater improvements than placebo in otherpain indices (present pain intensity and subject's perception ofdifferent neuropathic pain qualities), quality of life data (SF-36 andPOMS), and proportion of pain-free days.

Pharmacokinetics Results:

Trough and peak plasma drug concentrations during the Maintenance Phaseshowed a wide range of values, explained in part by the variability insubject weight and the low number of samples collected. At the 400mg/day dose, the mean plasma drug concentrations increased from 7.7μg/mL to 11.4 μg/mL (trough to peak, Visit 9) and from 7.9 μg/mL to 9.1μg/mL (Visit 10).

Safety Results:

The mean duration of exposure to study medication was 62.7 days forsubjects in the placebo treatment group and 59.6 days for subjects inthe SPM 927 treatment group indicating high tolerability to SPM 927.

The percentage of subjects who reported at least one treatment-emergentadverse event (TEAE) was higher in the SPM 927 treatment group, withoverall incidence rates of 87% of 60 subjects in the SPM 927 group and75% of 59 subjects in the placebo group.

Among all subjects, TEAEs were most common in the central and peripheralnervous system, with 46 subjects (39% of 119 subjects) reporting atleast one adverse event in this body system. However, adverse eventsassociated with the central and peripheral nervous system were reportedby comparable percentages of subjects in each treatment group (39% of 59placebo subjects, 38% of 60 SPM 927 subjects). Review of the adverseevent profile provided no evidence for an adverse effect on anyparticular body system.

Overall, headache (20% of 119 subjects), dizziness (12%), accident nototherwise specified (NOS) (11%), upper respiratory tract infection(10%), and nausea (9%) were the most frequently reported TEAEs. Ingeneral, the proportions of subjects who reported specific TEAEs, or whoreported TEAEs associated with particular body systems, were comparablebetween the placebo and SPM 927 treatment groups.

Overall, considerably more subjects first reported AEs during theTitration Phase compared with the Maintenance Phase and Taper/SafetyFollow-Up Phase. For most body systems, the number of subjects reportingAEs within each body system was greater during the Titration Phasecompared with the Maintenance Phase and Taper/Safety Follow-Up Phase.

No subjects died during this study. A total of 2 subjects reported 2serious adverse events during this study: one subject with one seriousadverse event (SAE) in the placebo treatment group (pain in right hipjudged to be not related to study medication) and one subject with oneSAE in the SPM 927 treatment group (abnormal electrocardiogram [ECG]judged to be unlikely related to study medication). A total of 8subjects (7% of 119 subjects) withdrew from the trial due to an AE: 3 inthe placebo group (5% of 59 subjects) and 5 in the SPM 927 group (8% of60 subjects).

Mean and median changes from baseline in hematology, clinical chemistryand coagulation, urinalysis, vital signs, and ECG parameters were small,within normal ranges, comparable between treatment groups, and not ofclinical concern. No safety issues with regards to QT or PR intervalwere identified during the study. HbA_(1C) levels changed only slightlyfrom Baseline to Visit 8 for the two treatment groups (mean changes of−0.1% and 0.1% for the placebo and SP 927 groups, respectively). Noimportant differences were observed in these parameters in thetransitions from Baseline to on-therapy values between the two treatmentgroups. Neurological examination findings at the end of the trialcompared with those at Baseline did not suggest any significant effectsdue to SPM 927.

Body weight changes during treatment with SPM 927 were small (−0,5 kgfor SPM 927 and 1,2 kg for placebo).

CONCLUSIONS

In summary, SPM 927 showed statistically significant and clinicallymeaningful efficacy in reducing neuropathic pain due to diabetic distalsensory polyneuropathy when titrated to a maintenance dose of 400mg/day. Overall, 60 subjects with painful diabetic neuropathy weretreated with SP 927 100-400 mg/day for up to 82 days; 46 of thesesubjects completed all phases of the trial. Analyses of safety data(adverse events, clinical laboratory evaluations, ECGs, vital signs, andphysical examinations) revealed no serious safety issues and support thefurther clinical development of SPM 927 as an agent to treat diabeticpatients with peripheral neuropathic pain.

SPM 927 did not induce weight gain which is an important property fordrugs administered to diabetic Type II patients. Some antidiabeticagents such as insulin and sulfonylureas are associated with weight gain(UKPDS 1998) and obesity is an established risk factor forcardiovascular disease (Schemthaner 1996).

1. Use of a compound having the Formula (Ib)

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl,aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkylheterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R isunsubstituted or is substituted with at least one electron withdrawinggroup or/and at least one electron donating group; R₁ is hydrogen orlower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl,heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted orsubstituted with at least one electron donating group or/and at leastone electron withdrawing group; R₂ and R₃ are independently hydrogen,lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo,heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lowercycloalkyl, lower cycloalkyl lower alkyl, or Z-Y wherein R₂ and R₃ maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; and whereinheterocyclic in R₂ and R₃ is furyl, thienyl, pyrazolyl, pyrrolyl,methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl,tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl,benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl,pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl,N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl,pyridyl, epoxy, aziridino, oxetanyl, azetidinyl or, when N is present inthe heterocyclic, an N-oxide thereof; Z is O, S, S(O)_(a), NR₄, NR₆′ orPR₄ or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl loweralkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocycliclower alkyl, lower alkyl heterocyclic and Y may be unsubstituted orsubstituted with at least one electron donating group or/and at leastone an electron withdrawing group, wherein heterocyclic has the samemeaning as in R₂ or R₃ and, provided that when Y is halo, Z is achemical bond, or ZY taken together is NR₄NR₅R₇, NR₄OR₅, ONR₄R₇, OPR₄R₅,PR₄OR₅, SNR₄R₇, NR₄SR₇, SPR₄R₅, PR₄SR₇, NR₄PR₅R₆, PR₄NR₅R₇, or N⁺R₅R₆R₇,

R₆′ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl which maybe unsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; R₄, R₅ and R₆ areindependently hydrogen, lower alkyl, aryl, aryl lower alkyl, loweralkenyl, or lower alkynyl, wherein R₄, R₅ and R₆ may independently beunsubstituted or substituted with at least one electron withdrawinggroup or/and at least one electron donating group; and R₇ is R₆ or COOR₈or COR₈, which R₇ may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;R₈ is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl oralkyl group may be unsubstituted or substituted with at least oneelectron withdrawing group or/and at least one electron donating group;and n is 1-4; and a is 1-3, or of a pharmaceutically acceptable saltthereof, for the preparation of a pharmaceutical composition useful forthe prevention, alleviation or/and treatment of pain associated withpainful diabetic neuropathy.
 2. Use according to claim 1, wherein thepain associated with painful diabetic neuropathy is a pain associatedwith diabetic distal sensory polyneuropathy.
 3. Use according to claim 1wherein one of R₂ and R₃ is hydrogen.
 4. Use according to claim 1wherein n is
 1. 5. Use according to claim 1 wherein one of R₂ and R₃ ishydrogen and n is
 1. 6. Use according to claim 1 wherein R is aryl loweralkyl and R₁ is lower alkyl.
 7. Use according to claim 1 wherein R₂ andR₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR₄ or PR₄; Yis hydrogen or lower alkyl or


8. Use according to claim 7 wherein R₂ is hydrogen and and R₃ is loweralkyl, or ZY; Z is O, NR₄ or PR₄; Y is hydrogen or lower alkyl;


9. Use according to claim 1 wherein R₂ is hydrogen and R₃ is loweralkyl, which may be substituted or unsubstituted with at least oneelectron donating group or/and at least one electron withdrawing group,NR₄OR₅, or ONR₄R₇.
 10. Use according to claim 1 wherein R₃ is loweralkyl which is unsubstituted or substituted with hydroxy or loweralkoxy,NR₄OR₅ or ONR₄R₇, wherein R₄, R₅ and R₇ are independently hydrogen orlower alkyl, R is aryl lower alkyl, which aryl group may beunsubstituted or substituted with at least one electron withdrawinggroup and R₁ is lower alkyl.
 11. Use according to claim 1 wherein arylis phenyl and is unsubstituted or substituted with halo.
 12. Useaccording to claim 1 wherein the compound is(R)-2-acetamido-N-benzyl-3-methoxy-propionamide;O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;N-acetyl-D-phenylglycinebenzylamide; D-1,2-(N,O-dimethylhydroxylamino)-2-acetamide acetic acid benzylamide; orD-1,2-(O-methylhydroxylamino)-2-acetamido acetic acid benzylamide. 13.Use of claim 1 wherein the compound has the Formula (Iib)

wherein Ar is phenyl which is unsubstituted or substituted with at leastone halo group; R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and R₁ is lower alkyl containing 1-3 carbon atoms or of apharmaceutically acceptable salt thereof.
 14. Use according to claim 13wherein Ar is unsubstituted phenyl.
 15. Use according to claim 13wherein halo is fluoro.
 16. Use according to claim 13 wherein R₃ isCH₂-Q, wherein Q is alkoxy containing 1-3 carbon atoms and Ar isunsubstituted phenyl.
 17. Use of claim 1 wherein the compund is in the Rconfiguration and has the formula

wherein R is benzyl which is unsubstituted or substituted with at leastone halo group; R₃ is CH₂-Q, wherein Q is lower alkoxy containing 1-3carbon atoms and R₁ is methyl or a pharmaceutically acceptable saltthereof.
 18. Use according to claim 17 which is substantiallyenantiopure.
 19. Use according to claim 17 wherein R is unsubstitutedbenzyl.
 20. Use according to claim 17 wherein halo is fluoro.
 21. Useaccording to claim 17 claim 1 wherein R₃ is CH₂-Q, wherein Q is alkoxycontaining 1-3 carbon atoms and R is unsubstituted benzyl.
 22. Useaccording to claim 1, wherein the compound of Formula (Ib) is(R)-2-Acetamido-N-benzyl-3-methoxypropionamide or a pharmaceuticallyacceptable salt thereof.
 23. Use according to claim 22 wherein thecompund is substantially enantiopure.
 24. Use according to claim 1,wherein the pharmaceutical composition is prepared for treatment withdoses of the compound of at least 100 mg/day, preferably of at least 200mg/day, more preferably of at least 300 mg/day, most preferably of atleast 400 mg/day.
 25. Use according to claim 1, wherein thepharmaceutical composition is prepared for treatment with doses of thecompound at a maximum of 6 g/day, preferably at a maximum of 3 g/day,more preferably of at a maximum 1 g/day and most preferably of at amaximum of 400 mg/day.
 26. Use according to claim 1, wherein thepharmaceutical composition is prepared for treatment with increasingdaily doses until a predetermined daily dose is reached which ismaintained during the further treatment.
 27. Use according to claim 1,wherein the pharmaceutical composition is prepared for treatment inthree doses per day, preferably two doses per day, more preferably in asingle dose per day.
 28. Use according to claim 1, wherein thepharmaceutical composition is prepared for an administration resultingin a plasma concentration of 0.1 to 15 μg/ml (trough) and 5 to 18.5μg/ml (peak), calculated as an average over a plurality of treatedsubjects.
 29. Use according to claim 1, wherein the pharmaceuticalcomposition is prepared for treatment for at least one week, preferablyat least two weeks, more preferably at least four weeks, most preferablyat least eight weeks.
 30. Use according to claim 1, wherein thepharmaceutical composition is prepared for oral administration.
 31. Useaccording to claim 1 wherein the pharmaceutical composition is usefulfor the prevention, alleviation or/and treatment of a conditionassociated with painful diabetic neuropathy which is average daily pain,overall pain, present pain intensity, pain interference with sleep, thesubjects' perception of pain interference with general activity, thepatients' global impression of change in pain, clinical globalimpression of change in pain, the subject's perception of differentneuropathic pain qualities, quality of life and proportion of pain-freedays.
 32. Use according to claim 1, wherein the painful diabeticneuropathy is associated with Diabetes mellitus Type I or Type II,preferably Diabetes mellitus Type II.
 33. Use according to claim 1,wherein the pharmaceutical composition further comprises an active agentfor the prevention, alleviation or/and treatment of Diabetes mellitusType I or II, preferably Diabetes mellitus Type II.
 34. Use according toclaim 33 wherein the pharmaceutical composition comprises a single doseform or comprises a separate dose form comprising a first compositioncomprising said compound and a second composition for the prevention,alleviation or/and the treatment of Diabetes mellitus Type I or Type II,preferably Diabetes mellitus Type II.
 35. Use according to claim 1wherein the pharmaceutical composition is prepared for administration inmammals.
 36. Use according to claim 35 wherein the pharmaceuticalcomposition is prepared for administration in humans.
 37. Apharmaceutical composition comprising (a) a compound as defined in claim1, and (b) an active agent for the prevention, alleviation or/andtreatment of Diabetes mellitus Type I or Type II, preferably Diabetesmellitus Type II.
 38. The pharmaceutical composition according to claim37 which is a single dose form or comprises a separate dose formcomprising a first composition comprising said compound and a secondcomposition for the prevention, alleviation or/and the treatment ofDiabetes mellitus Type I or Type II, preferably Diabetes mellitus TypeII.